Instalab ResearchAcross the SURPASS program of clinical trials, which collectively enrolled thousands of patients across multiple continents, tirzepatide delivered impressive results. In this head-to-head comparison against semaglutide, tirzepatide produced larger reductions in HbA1c and weight, in some cases by several kilograms more than semaglutide.
Patients lost as much as 12 kilograms of body weight and lowered their HbA1c by more than 2 percentage points, outcomes previously thought unreachable with a single medication. The SURMOUNT trials, which focused on obesity, confirmed tirzepatide’s ability to produce double-digit percentage weight loss, sometimes surpassing 20% of body weight in people without diabetes.
The numbers were not just statistically significant, they were clinically transformative. For patients struggling with both diabetes and obesity, tirzepatide offered something new: the possibility of getting blood sugar into near-normal ranges while simultaneously achieving substantial and sustained weight loss.
Despite its success, one barrier remains: tirzepatide is only available as a weekly injection. While once-weekly dosing is a major improvement over daily insulin, many patients still hesitate to begin injectable therapies. For some, the idea of needles is an emotional obstacle. For others, it is a matter of convenience or stigma.
This is where the possibility of an oral tirzepatide comes in. If a pill could deliver the same benefits as the injection, it might expand treatment to millions who would otherwise never start therapy. Oral semaglutide has already proven that incretin-based medications can be delivered in pill form. The question is whether tirzepatide, which is larger and more complex, can make the same leap.
Oral semaglutide provides a useful reference point. In large phase 3 trials, oral semaglutide did succeed in lowering blood glucose and reducing weight. However, the results were generally less dramatic than those seen with the injectable form. Absorption was inconsistent, and patients were required to follow strict instructions about fasting before and after dosing to ensure effectiveness.
If tirzepatide were developed in pill form, it would face the same challenges, perhaps even more so. Peptide drugs like GLP-1 and GIP agonists are notoriously unstable in the gastrointestinal tract. Protecting them from being broken down and ensuring they are absorbed into the bloodstream requires special delivery technology. While this is possible, it often comes with trade-offs in terms of potency, consistency, and cost.
At this point, it is important to draw a clear line between what we know and what we do not. Injectable tirzepatide has been studied in thousands of patients in rigorously designed randomized controlled trials. These studies show with strong statistical certainty that tirzepatide produces superior reductions in HbA1c and body weight compared with insulin, semaglutide, and placebo.
SURPASS-3 demonstrated that tirzepatide not only lowered HbA1c more effectively than insulin degludec but also caused significant weight loss, while insulin caused weight gain. SURPASS-4 extended these findings to patients at high cardiovascular risk, showing that tirzepatide reduced glucose without increasing major cardiovascular events.
In obesity-focused trials such as SURMOUNT-1 and SURMOUNT-2, tirzepatide produced the greatest weight loss ever seen in randomized obesity trials, with some patients losing more than one-fifth of their total body weight. These results were robust, statistically significant, and consistent across populations.
By contrast, there are currently no large-scale clinical trials proving the efficacy of oral tirzepatide. Research on oral formulations is still in its early stages. Any claims about oral tirzepatide must therefore remain speculative, extrapolated from the experience with oral semaglutide and the pharmacology of tirzepatide itself.
Tirzepatide is a large peptide molecule. When swallowed, enzymes in the stomach and intestines quickly break it down. Even if some survives digestion, very little can cross the intestinal wall into the bloodstream. Injectable formulations bypass this problem by delivering the drug directly under the skin.
Developing an oral form would require pairing tirzepatide with an absorption enhancer, protective carrier, or novel delivery technology. Oral semaglutide achieved this with SNAC, a molecule that temporarily alters the stomach environment to allow absorption. But even with this technology, oral semaglutide had variable uptake and required careful dosing instructions.
Given tirzepatide’s size and dual-receptor activity, it may be even more difficult to achieve consistent absorption orally. While this is not impossible, it is unlikely that an oral pill would perfectly match the pharmacokinetics of injections without losing some degree of potency.
Efficacy is not the only measure of value. Patient adherence, convenience, and willingness to initiate therapy matter just as much. Many patients who decline injections might accept an oral pill even if it were slightly less effective. From a public health perspective, the broader uptake could mean more people achieving at least partial benefits.
At the same time, patients who need the full potency of tirzepatide, such as those with advanced diabetes or severe obesity, may still benefit most from the injectable form. For them, the unparalleled outcomes seen in the SURPASS and SURMOUNT programs would likely outweigh the inconvenience of a weekly shot.
The injectable form of tirzepatide has already secured its place as one of the most effective therapies for diabetes and obesity. Oral tirzepatide, if successfully developed, would be a welcome addition, especially for patients hesitant about injections. But based on the pharmacological hurdles and lessons from oral semaglutide, it is unlikely that an oral pill will match injections in absolute effectiveness.
That said, “matching” injections may not be necessary for oral tirzepatide to make a major impact. Even a slightly less potent pill could help millions of patients who would otherwise avoid treatment altogether. In this way, oral and injectable tirzepatide would not compete so much as complement each other, giving patients and providers more options in the fight against diabetes and obesity.
